BMJ Open. 2023 May 30;13(5):e068915. doi: 10.1136/bmjopen-2022-068915.

ABSTRACT

OBJECTIVE: This study aims to understand the adverse drug reactions (ADRs) for non-statin antihyperlipidaemic drugs included in the China Anti-hyperlipidemic Drug Database.

DESIGN: An approach of Chinese national database analysis was employed to screen clinical trials involving non-statin antihyperlipidaemic drugs from 1989 to 2019.

SETTING: The database was provided by the China National Medical Products Administration Information Centre.

PARTICIPANTS: In total, 117 clinical studies with 8800 patients were selected from 2650 clinical trials of the Anti-hyperlipidemic Drug Database.

INTERVENTIONS: The non-statin antihyperlipidaemic drugs were divided into three groups: (1) fibrates (fenofibrate, gemfibrozil, bezafibrate, etofylline clofibrate); (2) nicotinic acid and derivatives (niacin, acipimox) and (3) others (probucol, cholestyramine).

RESULTS: The results of this study show that first, gastrointestinal symptoms were the most common reactions (6.975%), which account for approximately 50% of the reported cases with ADRs. Second, cholestyramine (16.418%) and gemfibrozil (13.158%) were the most common gastrointestinal side effect-causing non-statin antihyperlipidaemic drugs, which account for one-third of the population. Third, niacin (7.879%) and gemfibrozil (5.000%) were the most likely cause of liver disease symptoms. Finally, niacin (10.909%) and acipimox (18.847%) were the major non-statin antihyperlipidaemic drugs with skin symptoms.

CONCLUSION: This study revealed that gastrointestinal symptoms were the most common ADRs of fibrates, probucol and cholestyramine in the Chinese population. For nicotinic acid and derivatives, the ADRs of skin symptoms were the most common in China.

PMID:37253501 | DOI:10.1136/bmjopen-2022-068915

BMJ. 2023 May 30;381:e074678. doi: 10.1136/bmj-2022-074678.

ABSTRACT

OBJECTIVE: To develop and validate a prognostic model to inform risk stratified decisions on frequency of monitoring blood tests during long term methotrexate treatment.

DESIGN: Retrospective cohort study.

SETTING: Electronic health records within the UK's Clinical Practice Research Datalink (CPRD) Gold and CPRD Aurum.

PARTICIPANTS: Adults (≥18 years) with a diagnosis of an immune mediated inflammatory disease who were prescribed methotrexate by their general practitioner for six months or more during 2007-19.

MAIN OUTCOME MEASURE: Discontinuation of methotrexate owing to abnormal monitoring blood test result. Patients were followed-up from six months after their first prescription for methotrexate in primary care to the earliest of outcome, drug discontinuation for any other reason, leaving the practice, last data collection from the practice, death, five years, or 31 December 2019. Cox regression was performed to develop the risk equation, with bootstrapping used to shrink predictor effects for optimism. Multiple imputation handled missing predictor data. Model performance was assessed in terms of calibration and discrimination.

RESULTS: Data from 13 110 (854 events) and 23 999 (1486 events) participants were included in the development and validation cohorts, respectively. 11 candidate predictors (17 parameters) were included. In the development dataset, the optimism adjusted R2 was 0.13 and the optimism adjusted Royston D statistic was 0.79. The calibration slope and Royston D statistic in the validation dataset for the entire follow-up period was 0.94 (95% confidence interval 0.85 to 1.02) and 0.75 (95% confidence interval 0.67 to 0.83), respectively. The prognostic model performed well in predicting outcomes in clinically relevant subgroups defined by age group, type of immune mediated inflammatory disease, and methotrexate dose.

CONCLUSION: A prognostic model was developed and validated that uses information collected during routine clinical care and may be used to risk stratify the frequency of monitoring blood test during long term methotrexate treatment.

PMID:37253479 | DOI:10.1136/bmj-2022-074678

Front Endocrinol (Lausanne). 2023 May 11;14:1157805. doi: 10.3389/fendo.2023.1157805. eCollection 2023.

ABSTRACT

Immune checkpoint inhibitors (ICIs) have increasingly been the mainstay of treatment for numerous malignancies. However, due to their association with autoimmunity, ICIs have resulted in a variety of side effects that involve multiple organs including the endocrine system. In this review article, we describe our current understanding of the autoimmune endocrinopathies as a result of the use of ICIs. We will review the epidemiology, pathophysiology, clinical presentation, diagnosis, and management of the most commonly encountered endocrinopathies, including thyroiditis, hypophysitis, Type 1 diabetes, adrenalitis, and central diabetes insipidus.

PMID:37251665 | PMC:PMC10210589 | DOI:10.3389/fendo.2023.1157805

Zhonghua Gan Zang Bing Za Zhi. 2023 Apr 20;31(4):440-444. doi: 10.3760/cma.j.cn501113-20220309-00105.

ABSTRACT

Drug-induced liver injury (DILI) is one of the most common adverse drug reactions that may seriously threaten the health of children and is receiving increasing clinical attention day by day. There is still no independent diagnosis and treatment guideline for DILI in children, but its clinical features are not completely similar to those in adults. This article reviews the epidemiology, clinical features, diagnosis, and treatment progress in order to provide a reference for the management of DILI in children.

PMID:37248985 | DOI:10.3760/cma.j.cn501113-20220309-00105

Zhonghua Gan Zang Bing Za Zhi. 2023 Apr 20;31(4):355-384. doi: 10.3760/cma.j.cn501113-20230419-00176-1.

ABSTRACT

Drug-induced liver injury (DILI) is an important adverse drug reaction that can lead to acute liver failure or even death in severe cases. Currently, the diagnosis of DILI still follows the strategy of exclusion. Therefore, a detailed history taking and a thorough and careful exclusion of other potential causes of liver injury is the key to correct diagnosis. This guideline was developed based on evidence-based medicine provided by the latest research advances and aims to provide professional guidance to clinicians on how to identify suspected DILI timely and standardize the diagnosis and management in clinical practice. Based on the clinical settings in China, the guideline also specifically focused on DILI in chronic liver disease, drug-induced viral hepatitis reactivation, common causing agents of DILI (herbal and dietary supplements, anti-tuberculosis drugs, anti-neoplastic drugs), and signal and assessment of DILI in clinical trials.

PMID:37248976 | DOI:10.3760/cma.j.cn501113-20230419-00176-1

J Dermatolog Treat. 2023 Dec;34(1):2213364. doi: 10.1080/09546634.2023.2213364.

ABSTRACT

Background: Isotretinoin is frequently used for treatment of severe nodulocystic and papulopustular acne, however use is limited by mucocutaneous, ocular, and systemic side effects.Objective: (1) provide a systematic meta-analysis of ocular side effects during isotretinoin use and their corresponding incidences; (2) provide a narrative summary of ocular side effects during isotretinoin use reported in case reports.Methods: A systematic database search using predefined search terms was performed in PubMed, EMBASE, and Scopus from inception to 5 March, 2021. Predetermined inclusion and exclusion criteria were used to select included studies. In total, 53 original studies qualified for meta-analysis, and 41 case reports/series qualified for narrative results.Results: The studies included in the meta-analysis reported incidences of various ocular side effects including dry eye, eye sensitivity, vision changes, and ocular inflammatory conditions. Incidences across studies did vary, leading to considerable heterogeneity. The narrative results summarize more uncommon, but equally important, ocular side effects.Conclusions: Dry eye is the most commonly reported ocular side effect. Other less common, but more serious, ocular side effects including vision changes can occur. We recommend that isotretinoin prescribers monitor for dry eye. Limitations include the heterogeneity of reported incidences of ocular side effects between studies.

PMID:37248700 | DOI:10.1080/09546634.2023.2213364

Cureus. 2023 Apr 25;15(4):e38109. doi: 10.7759/cureus.38109. eCollection 2023 Apr.

ABSTRACT

Isolated uvulitis is a rare but potentially devastating condition that can result in airway compromise. Etiologies include infection, trauma, allergy, primary angioedema, immunologic disorders, and inhalation injury. Uvulitis has been previously reported as a reaction to inhalation of cannabis, crack cocaine, and mephedrone. We present a case of isolated uvulitis with concerns for impending airway obstruction in a patient after smoking fentanyl. While a sore throat is a common chief complaint among ED patients, emergency providers should consider uvulitis within this deadly differential.

PMID:37252458 | PMC:PMC10212724 | DOI:10.7759/cureus.38109

Front Psychiatry. 2023 May 12;14:1142531. doi: 10.3389/fpsyt.2023.1142531. eCollection 2023.

ABSTRACT

INTRODUCTION: Benzodiazepines (BZs) are prescribed as anxiolytics, but their use is limited by side effects including abuse liability and daytime drowsiness. Neuroactive steroids are compounds that, like BZs, modulate the effects of GABA at the GABAA receptor. In a previous study, combinations of the BZ triazolam and neuroactive steroid pregnanolone produced supra-additive (i.e., greater than expected effects based on the drugs alone) anxiolytic effects but infra-additive (i.e., lower than expected effects based on the drugs alone) reinforcing effects in male rhesus monkeys, suggestive of an improved therapeutic window.

METHODS: Female rhesus monkeys (n=4) self-administered triazolam, pregnanolone, and triazolam-pregnanolone combinations intravenously under a progressive-ratio schedule. In order to assess characteristic sedative-motor effects of BZ-neuroactive steroid combinations, female rhesus monkeys (n=4) were administered triazolam, pregnanolone, and triazolam-pregnanolone combinations. Trained observers, blinded to condition, scored the occurrence of species-typical and drug-induced behaviors.

RESULTS: In contrast to our previous study with males, triazolam-pregnanolone combinations had primarily supra-additive reinforcing effects in three monkeys but infra-additive reinforcing effects in one monkey. Scores for deep sedation (i.e., defined as atypical loose-limbed posture, eyes closed, does not respond to external stimuli) and observable ataxia (any slip, trip, fall, or loss of balance) were significantly increased by both triazolam and pregnanolone. When combined, triazolam-pregnanolone combinations had supra-additive effects for inducing deep sedation, whereas observable ataxia was attenuated, likely due to the occurrence of robust sedative effects.

DISCUSSION: These results suggest that significant sex differences exist in self-administration of BZ-neuroactive steroid combinations, with females likely to show enhanced sensitivity to reinforcing effects compared with males. Moreover, supra-additive sedative effects occurred for females, demonstrating a higher likelihood of this adverse effect when these drug classes are combined.

PMID:37252149 | PMC:PMC10213563 | DOI:10.3389/fpsyt.2023.1142531

Heliyon. 2023 May 2;9(5):e15795. doi: 10.1016/j.heliyon.2023.e15795. eCollection 2023 May.

ABSTRACT

INTRODUCTION: People-centered care (PCC) strategies are believed to improve overall health outcomes. Medicines use is essential for the treatment of many patients with chronic conditions. Non-adherence rates are high and result in poor health outcomes, and increased healthcare utilization and costs. This study aimed to explore the relationship between PCC and adherence to medicines for persons with chronic medicines use, as well as the extent to which patients' beliefs about medicines are influenced by their level of perceived PCC.

METHODS: A cross-sectional survey design was performed with adults using at least 3 chronic medicines per day. To measure the degree of medicines adherence, patients' ideas about medication, and PCC, four validated questionnaires were used: The Medication Adherence Report Scale (MARS-5), Beliefs about medicines questionnaire (BMQ), Client-Centered Care Questionnaire (CCCQ) and the Shared Decision Making Questionnaire (SDM-Q-9). Socio-demographics, health status, and drug-related burden were questioned as potential factors to impact the relationship between PCC and adherence.

RESULTS: A sample of 459 persons participated. The mean score on the CCCQ (adjusted to pharmacotherapy) was 52.7 on 75 (sd = 8.83, range [18-70]). The top 20% scored 60 or more, the 20% lowest scores were 46 or less. Adherence levels were high, with a mean score of 22.6 on 25 on the MARS-5, and 88% scoring 20 or more. An increase in PCC corresponded to a higher chance of medicines adherence (OR 1.07, 95%CI [1.02-1.12]), corrected for age, the burden due to chronic diseases, the impact of side effects on daily life, and participants' beliefs about medicines. PCC showed positive correlations with the necessity of medicines use (r = 0.1, p = 0.016) and the balance between necessity and concerns (r = 0.3, p < 0.001); and negative correlations with levels of concerns (r = -0.3, p < 0.001) and scores on harmfulness (r = -0.3, p < 0.001) and overuse of medicines (r = -0.4, p < 0.001).

CONCLUSION: Patients with chronic medicine use perceived an average high level of people-centeredness in the pharmaceutical care they received. This PCC was weakly positively associated with adherence to their medicines. The higher PCC was evaluated, the more patients believed in the necessity of the medicines use and the better the balance between necessity and concerns. The people-centeredness of pharmaceutical care showed several shortcomings and can still be improved. As such, healthcare providers are advised to actively engage in PCC, and not to wait passively for information provided by the patient.

PMID:37251820 | PMC:PMC10208933 | DOI:10.1016/j.heliyon.2023.e15795

EClinicalMedicine. 2023 May 18;60:101993. doi: 10.1016/j.eclinm.2023.101993. eCollection 2023 Jun.

ABSTRACT

BACKGROUND: Radium-223, a targeted alpha therapy, is approved to treat bone-dominant metastatic castration-resistant prostate cancer (mCRPC), based on significantly prolonged overall survival versus placebo and a favourable safety profile in the phase 3 ALSYMPCA study. ALSYMPCA was conducted when few other treatment options were available, and prospectively collected data are limited on the use of radium-223 in the current mCRPC treatment landscape. We sought to understand long-term safety and treatment patterns in men who received radium-223 in real-world clinical practice.

METHODS: REASSURE (NCT02141438) is a global, prospective, observational study of radium-223 in men with mCRPC. Primary outcomes are adverse events (AEs), including treatment-emergent serious AEs (SAEs) and drug-related AEs during and ≤30 days after radium-223 completion, grade 3/4 haematological toxicities ≤6 months after last radium-223 dose, drug-related SAEs after radium-223 therapy completion, and second primary malignancies.

FINDINGS: Data collection commenced on Aug 20, 2014, and the data cutoff date for this prespecified interim analysis was Mar 20, 2019 (median follow-up 11.5 months [interquartile range 6.0-18.6]), 1465 patients were evaluable. For second primary malignancies, 1470 patients were evaluable, 21 (1%) of whom had a total of 23 events. During radium-223 therapy, 311 (21%) of 1465 patients had treatment-emergent SAEs, and 510 (35%) had drug-related AEs. In the 6 months after completion of radium-223 therapy, 214 (15%) patients had grade 3/4 haematological toxicities. Eighty patients (5%) had post-treatment drug-related SAEs. Median overall survival was 15.6 months (95% confidence interval 14.6-16.5) from radium-223 initiation. Patient-reported pain scores declined or stabilised. Seventy (5%) patients had fractures.

INTERPRETATION: REASSURE offers insight into radium-223 use in global real-world clinical practice with currently available therapies. At this interim analysis, with a median follow-up of almost 1 year, 1% of patients had second primary malignancies, and safety and overall survival findings were consistent with clinical trial experience. Final analysis of REASSURE is due in 2024.

FUNDING: Bayer HealthCare.

PMID:37251627 | PMC:PMC10209672 | DOI:10.1016/j.eclinm.2023.101993

Front Pharmacol. 2023 May 12;14:1161897. doi: 10.3389/fphar.2023.1161897. eCollection 2023.

ABSTRACT

Background: Hemodialysis patients have a high risk of severe/critical COVID-19 and related high mortality, but nirmatrelvir/ritonavir is not recommended for hemodialysis patients with COVID-19 infection because of lack of evidence of safety. Objectives: Our study aims to evaluate the minimum plasma concentration (Cmin) of nirmatrelvir and its safety of different doses of nirmatrelvir/ritonavir in hemodialysis patients with mild COVID-19. Method: This was a prospective, two step, nonrandomized, open-label study. Participants were treated with nirmatrelvir 150 mg or 300 mg once a day (another 75 mg or 150 mg supplied after hemodialysis) and ritonavir 100 mg twice daily for 5 days, respectively. The primary outcome was the safety of nirmatrelvir/ritonavir, including the Cmin of nirmatrelvir and the number of adverse events (AE). The secondary outcome was the time of viral elimination in hemodialysis patients. Results: Adverse events were happened in 3 and 7 participants in the step 1 and step 2 group, respectively (p = 0.025). Among them, 2 and 6 participants were identified as drug-related adverse events (p = 0.054). No SAE or liver function damage happened. The Cmin of nirmatrelvir in step 1 and step 2 group were 5,294.65 ± 2,370.59 ng/mL and 7,675.67 ± 2,745.22 ng/mL (p = 0.125). The Cmin of the control group was 2,274.10 ± 1,347.25 ng/mL (p = 0.001 compared to step 2 and p = 0.059 compared to step 1). Compared to hemodialysis patients without nirmatrelvir/ritonavir, there were no statistical differences in overall viral elimination time (p = 0.232). Conclusion: In our study, two doses of nirmatrelvir/ritonavir appeared to be excessive for hemodialysis patients. Although all of the patients tolerated 5-day administration, nearly half of the patients experienced drug-related adverse events. In addition, the medication group did not show a significant advantage in the time of viral elimination.

PMID:37251313 | PMC:PMC10213535 | DOI:10.3389/fphar.2023.1161897

Viruses. 2023 May 17;15(5):1181. doi: 10.3390/v15051181.

ABSTRACT

OBJECTIVE: The main goal of this study was to assess the potential clinical impact of an outpatient administration of available antivirals including SOT, N/R, and MOL to COVID-19 patients at high risk for disease progression.

METHODS: We conducted a retrospective analysis on 2606 outpatient individuals with mild to moderate COVID-19 at risk for disease progression, hospitalization, or death. After receiving either SOT (420/2606), MOL (1788/2606), or N/R (398/2606), patients were followed-up with regarding primary (hospitalization rate) and secondary (treatment and side effects) outcomes by phone.

RESULT: A total of 2606 patients were treated at the outpatient clinic (SOT: 420; N/R: 398; MOL: 1788). 3.2% of the SOT patients (1 ICU admission), 0.8% of the MOL patients (2 ICU admissions), and none of the N/R patients were hospitalized. 14.3% of the N/R patients reported strong to severe side effects, exceeding SOT (2.6%) and MOL (5%) patients. A reduction in COVID symptoms after the treatment was experienced by 43% of patients in both the SOT and MOL groups and by 67% of patients in the N/R group, respectively. Women had a higher chance of symptom improvement with MOL (OR 1.2, 95%CI 1.0-1.5).

CONCLUSION: All antiviral treatment options effectively prevented hospitalization in high-risk COVID-19 patients and were well tolerated. Side effects were pronounced in patients with N/R.

PMID:37243267 | PMC:PMC10224114 | DOI:10.3390/v15051181

Nutrients. 2023 May 13;15(10):2298. doi: 10.3390/nu15102298.

ABSTRACT

The increased consumption of a variety of herbs/supplements has been raising serious health concerns. Owing to an inadequate understanding of herb/supplement-drug interactions, the simultaneous consumption of these products may result in deleterious effects and, in extreme cases, even fatal outcomes. This systematic review is aimed at understanding the knowledge and beliefs about the consumption of herbs/supplements and herb/drug-supplement interactions (HDIs). The study follows the PRISMA guidelines. Four online databases (Web of Science; PubMed; Cochrane; and EBSCOhost) were searched, and a total of 44 studies were included, encompassing 16,929 participants. Herb and supplement consumption is explained mostly by the reported benefits across multiple conditions and ease of use. Regarding HDIs, most people take both herbs/supplements and prescription drugs simultaneously. Only a small percentage of participants have knowledge about their interaction effects, and many reported adverse interactions or side effects. Nevertheless, the main reason for stopping the prescribed drug intake is the perceived lack of its effect, and not due to interactions. Therefore, it is important to increase the knowledge about supplement use so that further strategies can be elaborated to better detect or be alert for whenever a potentially dangerous reaction and/or interaction may occur. This paper raises awareness regarding the need for developing a decision support system and ends with some considerations about the development of a technological solution capable of detecting HDIs and, thereby, aiding in the improvement of pharmacy services.

PMID:37242184 | PMC:PMC10220613 | DOI:10.3390/nu15102298

BMC Nephrol. 2023 May 26;24(1):149. doi: 10.1186/s12882-023-03210-5.

ABSTRACT

BACKGROUND: Chronic kidney disease (CKD) is a major public health concern due to its high mortality risk, high hospitalization rates and cost, and low life expectancy. Thus, CKD patients are among patient group that may benefit from clinical pharmacy services the most.

METHODS: This was a prospective interventional study conducted between October 1, 2019, and March 18, 2020, in the nephrology ward of Ankara University School of the Medicine, Ibn-i Sina Hospital. DRPs were classified according to PCNE v8.03. The main outcomes were interventions proposed and the rate of acceptance by the physicians.

RESULTS: 269 pre-dialysis patients were included to determine DRPs during the treatment process of the patients. 205 DRPs were found in 131 (48.7%) patients. Treatment efficacy was found to be the main type of DRPs (56.2%) followed by treatment safety (39.6%). When patients with and without DRPs were compared, it was found that the number of female patients (55.0%) was higher in the group with DRPs (p < 0.05). The length of hospital stays (11.3 ± 7.7) and the mean number of drugs used (9.6 ± 3.6) in the group with DRPs were significantly higher than those without DRPs (9.3 ± 5.9; 8.1 ± 3.5, respectively) (p < 0.05). 91.7% of the interventions were accepted by the physicians, and patients and found clinically beneficial. 71.7% of DRPs were fully resolved, 1.9% partially resolved and 23.4% could not be resolved.

CONCLUSIONS: A high prevalence of DRPs in patients with chronic kidney disease was determined during therapy. Clinical pharmacist interventions were highly accepted by the physicians and patients. This may indicate implementation of clinical pharmacy services in the nephrology ward has a great impact on optimized therapy and prevention DRPs.

PMID:37237342 | PMC:PMC10224574 | DOI:10.1186/s12882-023-03210-5

Curr Oncol. 2023 May 3;30(5):4700-4723. doi: 10.3390/curroncol30050355.

ABSTRACT

Immune-checkpoint inhibitors (ICIs) are immunomodulatory monoclonal antibodies, which increase antitumor immunity of the host and facilitate T-cell-mediated actions against tumors. These medications have been used in recent years as a weapon against advanced stage malignancies, such as melanoma, renal cell carcinoma, lymphoma, small or non-small cell lung cancer, and colorectal cancer. Unfortunately, they are not free from possible adverse effects (immune-related adverse events-irAEs) that mainly affect skin, gastrointestinal, hepatic, and endocrine systems. Early diagnosis of irAEs is essential to correctly and rapidly manage patients, with ICIs suspension and therapies administration. Deep knowledge of the imaging and clinical patterns of irAEs is the key to promptly rule out other diagnoses. Here, we performed a review of the radiological signs and differential diagnosis, based on the organ involved. The aim of this review is to provide guidance to recognize the most significant radiological findings of the main irAEs, based on incidence, severity, and the role of imaging.

PMID:37232813 | PMC:PMC10217557 | DOI:10.3390/curroncol30050355

Int J Mol Med. 2023 Jul;52(1):55. doi: 10.3892/ijmm.2023.5258. Epub 2023 May 26.

ABSTRACT

The side effects of chemotherapy drugs have been hindering the progress of tumor treatment. The liver is the metabolic site of most drugs, which leads to the frequent occurrence of liver injury. Classical chemotherapy drugs such as pirarubicin (THP) can also cause dose‑dependent hepatotoxicity, and the related mechanism is closely related to liver inflammation. Scutellarein (Sc) is a potential Chinese herbal monomer exhibiting liver protection activity, which can effectively alleviate the liver inflammation caused by obesity. In the present study, THP was used to establish a rat model of hepatotoxicity, and Sc was used for treatment. The experimental methods used included measuring body weight, detecting serum biomarkers, observing liver morphology with H&E staining, observing cell apoptosis with TUNEL staining, and detecting the expression of PTEN/AKT/NFκB signaling pathways and inflammatory genes with PCR and western blotting. However, whether Sc can inhibit the liver inflammation induced by THP has not been reported. The experimental results showed that THP led to the upregulation of PTEN and the increase of inflammatory factors in rat liver, while Sc effectively alleviated the aforementioned changes. It was further identified in primary hepatocytes that Sc can effectively inhabited PTEN, regulate AKT/NFκB signaling pathway, inhibit liver inflammation and ultimately protect the liver.

PMID:37232353 | DOI:10.3892/ijmm.2023.5258

Oncotarget. 2023 May 26;14:543-560. doi: 10.18632/oncotarget.28447.

ABSTRACT

The long non-coding RNA (lncRNA) MALAT1 is a regulator of oncogenesis and cancer progression. MAPK-pathway upregulation is the main event in the development and progression of human cancer, including melanoma and recent studies have shown that MALAT1 has a significant impact on the regulation of gene and protein expression in the MAPK pathway. However, the role of MALAT1 in regulation of gene and protein expression of the MAPK-pathway kinases RAS, RAF, MEK and ERK in melanoma is largely unknown. We demonstrate the impacts of antisense oligonucleotide (ASO)-based MALAT1-inhibition on MAPK-pathway gene regulation in melanoma. Our results showed that MALAT1-ASO treatment decreased BRAF RNA expression and protein levels, and MALAT1 had increased correlation with MAPK-pathway associated genes in melanoma patient samples compared to healthy skin. Additionally, drug-induced MAPK inhibition upregulated MALAT1-expression, a finding that resonates with a paradigm of MALAT1-expression presented in this work: MALAT1 is downregulated in melanoma and other cancer types in which MALAT1 seems to be associated with MAPK-signaling, while MALAT1-ASO treatment strongly reduced the growth of melanoma cell lines, even in cases of resistance to MEK inhibition. MALAT1-ASO treatment significantly inhibited colony formation in vitro and reduced tumor growth in an NRAS-mutant melanoma xenograft mouse model in vivo, while showing no aberrant toxic side effects. Our findings demonstrate new insights into MALAT1-mediated MAPK-pathway gene regulation and a paradigm of MALAT1 expression in MAPK-signaling-dependent cancer types. MALAT1 maintains essential oncogenic functions, despite being downregulated.

PMID:37235843 | DOI:10.18632/oncotarget.28447

Medicine (Baltimore). 2023 May 26;102(21):e33859. doi: 10.1097/MD.0000000000033859.

ABSTRACT

RATIONALE: Immune-related adverse events are occasionally reported in Sintilimab treatment. This study reports a forward and reverse swelling case along the vein after infusion of Sintilimab. At present, swelling along the vascular direction during peripheral infusion are limitedly reported at home and abroad, especially when choosing a vein with thick, elastic, and good blood return.

PATIENT CONCERNS: A 56-year-old male who suffered from esophageal cancer and liver cancer and received albumin-bound paclitaxel and nedaplatin chemotherapy in combination with Sintilimab immunotherapy appeared swelling along the vessel after infusion of Sintilimab. The patient was punctured 3 times.

DIAGNOSES: Sintilimab-induced vascular edema may be a side effect resulted from a combination of variables such as relatively poor vascular function of the patient, chemical extravasation, allergic skin reactions, venous valves, vascular intima, and diameter stenosis. Sintilimab rarely causes vascular edema only when drug allergic reaction is the underlying factor. As only a few cases of vascular edema caused by Sintilimab have been reported, causes to such a drug-induced vascular edema remained unclear.

INTERVENTIONS: The swelling was controlled by an intravenous specialist nurse according to delayed extravasation treatment and the doctor anti-allergy treatment, but the uncertainty of repeated puncture and symptom diagnosis caused pain and anxiety to the patient and his family.

OUTCOMES: The symptom of swelling was gradually relieved after the anti-allergic treatment. The patient completed the following drug infusion without discomfort after the third puncture. When the patient was discharged the next day, swelling in his both hands disappeared, and the patient had no anxiety or discomfort.

LESSONS: The side effects of immunotherapy may accumulate over time. Early identification and appropriate nursing management are the keys to minimizing patients' pain and anxiety. To effectively treat symptoms, nurses could benefit from quickly identifying the source of swelling.

PMID:37233405 | DOI:10.1097/MD.0000000000033859

Diabetes Obes Metab. 2023 May 25. doi: 10.1111/dom.15099. Online ahead of print.

ABSTRACT

AIMS: Albuminuria is associated with abnormalities in the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate pathway. We assessed safety and efficacy of the NO-independent sGC activator BI 685509 in patients with diabetic kidney disease and albuminuria.

MATERIALS AND METHODS: In this Phase Ib trial (NCT03165227), we randomized patients with type 1 or 2 diabetes, estimated glomerular filtration rate (eGFR) 20-75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200-3500 mg/g to oral BI 685509 (1 mg three times daily, n = 20; 3 mg once daily, n = 19; 3 mg three times daily, n = 20, after final titration) or placebo (n = 15) for 28 days. Changes from baseline in UACR in first morning void (UACRFMV ) and 10-hour (UACR10h ) urine (3 mg once daily/three times daily only) were assessed.

RESULTS: Baseline median eGFR and UACR were 47.0 mL/min/1.73 m2 and 641.5 mg/g, respectively. Twelve patients had drug-related adverse events (AEs; 16.2%: BI 685509, n = 9; placebo, n = 3), most frequently hypotension (4.1%: BI 685509, n = 2; placebo, n = 1) and diarrhoea (2.7%: BI 685509, n = 2; placebo, n = 0). Four patients experienced AEs leading to study discontinuation (5.4%: BI 685509, n = 3; placebo, n = 1). Placebo-corrected mean UACRFMV decreased from baseline in the 3-mg once-daily (28.8%, P = 0.23) and three-times-daily groups (10.2%, P = 0.71) and increased in the 1-mg three-times-daily group (6.6%, P = 0.82); changes were not significant. UACR10h decreased by 35.3% (3 mg once daily, P = 0.34) and 56.7% (3 mg three times daily, P = 0.09); ≥50.0% of patients (UACR10h 3 mg once daily/three times daily) responded (≥20% UACR decrease from baseline).

CONCLUSIONS: BI 685509 was generally well tolerated. Effects on UACR lowering merit further investigation.

PMID:37232058 | DOI:10.1111/dom.15099

HIV Med. 2023 May 25. doi: 10.1111/hiv.13501. Online ahead of print.

ABSTRACT

OBJECTIVE: We hypothesized that total body weight (TBW) gain after switching antiretroviral therapy (ART) regimen to tenofovir disoproxil fumarate/lamivudine/dolutegravir (TLD) may negatively impact ART adherence and viral load (VL) and therefore sought to examine these associations.

METHODS: The ongoing African Cohort Study (AFRICOS) enrols people with HIV at 12 facilities in Kenya, Nigeria, Tanzania and Uganda supported by The US President's Emergency Plan for AIDS Relief. Among ART-experienced participants who switched to TLD, we used multivariable multinomial logistic regression to examine associations between pre-/post-TLD changes in percentage TBW (≥5% gain, <5% change, ≥5% loss) and changes in self-reported ART adherence (0, 1-2, ≥3 days missed doses in past 30 days) and VL [(<50 copies/mL (undetectable), 50-999 copies/mL (detectable, but suppressed), ≥1000 copies/mL (unsuppressed)].

RESULTS: Among 1508 participants, median time from starting TLD to follow-up was 9 months (interquartile range: 7-11). Overall, 438 (29.1%) participants experienced a TBW gain ≥5%, which was more common among females than among males (32.2% vs 25.2%, p = 0.005) and participants switching from efavirenz [32.0% vs nevirapine (19.9%) and boosted protease inhibitor (20.0%); p < 0.001]. Compared with a TBW change <5% [950 (63.0%) participants], TBW gain ≥5% was not significantly associated with more days with missed ART doses [adjusted odds ratio (aOR) = 0.77, 95% confidence interval (CI): 0.48-1.23] or VL becoming detectable and/or unsuppressed (aOR = 0.69, 95% CI: 0.41-1.16).

CONCLUSIONS: Although a substantial proportion of participants experienced weight gain after switching to TLD, we did not identify a significant impact on adherence or virological outcomes.

PMID:37232057 | DOI:10.1111/hiv.13501